Cardiovascular disease is a major health risk throughout the industrialized world. Atherosclerosis, the most prevalent of inflammation-mediated cardiovascular diseases, is the principal cause of heart attack, stroke, and gangrene of the extremities, and thereby the principle cause of death in the United States. Atherosclerosis is a complex disease involving many cell types and molecular factors. The process, in normal circumstances, is a protective response to insults to the endothelium and smooth muscle cells (SMCs) of the wall of the artery, consists of the formation of fibrofatty and fibrous lesions or plaques, preceded and accompanied by inflammation. The advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive inflammatory-fibroproliferative response to numerous different forms of insult. For example, shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.
Atherosclerosis is thought to also involve inflammation, because certain white blood cells—lymphocytes, monocytes, and macrophages—are present throughout the development of atherosclerosis. These cells usually gather only when inflammation develops. Atherosclerosis begins when monocytes are activated and move out of the bloodstream into the wall of an artery. There, they are transformed into foam cells, which collect cholesterol and other fatty materials. In time, these fat-laden foam cells accumulate and form atheromas in the lining of the artery's wall, causing a thickening and hardening of the wall. Atheromas may be scattered throughout medium-sized and large arteries, but usually form where the arteries branch—presumably because the constant turbulent blood flow at these areas injures the artery's wall, making these areas more susceptible to atheroma formation.
The deposition for cardiovascular disease, such as atherosclerosis, is slow and starts at an early age. Clinical symptoms may take years to manifest themselves and are very serious, including coronary heart disease and stroke. Generally, the disease process will have begun long before these clinical manifestations appear. Therefore it is desirable to have available a diagnostic technique which provides an early warning of the onset of the deposition for cardiovascular disease, such as atherosclerosis.
Relevant Literature
U.S. Pat. Nos. 6,316,196, 6,576,753, 6,939,674; U.S. Patent Application Publication Nos. 2003/0224418, 2004/0209288 2006/0019269, and 2005/0113408; Helgadottir et al., A. J. Human Genetics 76:505-509 (2005); Helgadottir et al., Nature Gentetics 36:233-239 (2004); Helgadottir et al., Nature Genetics 38(1):68-74 (2006); Mehrabian et al., Circ Res. 98(9):e68 (2006); Mehrabian et al., Circ Res. 91(2):120-6 (2002); and Dwyer et al., N Engl J Med. 350(1):29-37 (2004).